Protected syn-Aldol Compounds from Direct, Catalytic, and Enantioselective Reactions of N-Acyl-1,3-oxazinane-2-thiones with Aromatic Acetals

A direct and asymmetric syn-aldol reaction of N-acyl-1,3-oxazinane-2-thiones with dialkyl acetals from aromatic acetals in the presence of 2–5 mol % [DTBM-SEGPHOS]NiCl2, TMSOTf, and lutidine has been developed. It has been established that the oxazinanethione heterocycle, used for the first time as a scaffold in asymmetric carbon–carbon bond-forming reactions, can be smoothly removed to give access to a variety of enantiomerically pure compounds with high synthetic value.

The reaction mixture was quenched with sat NH4Cl (2 mL) and partitioned in CH2Cl2 (15 mL) and water (15 mL). The aqueous layer was extracted with CH2Cl2 (2  15 mL). The combined organic extracts were dried (Na2SO4), and concentrated. The resultant residue was analyzed by 1 H NMR (400 MHz).
Both the diastereoselectivity (dr) and conversion are summarized in Table SI-1. Eventually, the crude mixture was purified by flash column chromatography to afford the formed products and characterize them properly. Protected syn Aldol Compounds from Direct,thiones to Aromatic Acetals S12
The reaction mixture was quenched with sat NH4Cl (2 mL) and partitioned in CH2Cl2 (15 mL) and water (15 mL). The aqueous layer was extracted with CH2Cl2 (2  15 mL). The combined organic extracts were dried (Na2SO4), and concentrated. The resultant residue was analyzed by 1 H NMR (400 MHz).
Both the diastereoselectivity (dr) and conversion are summarized in Table SI-2.  Direct,thiones to Aromatic Acetals S13
The reaction mixture was quenched with saturated NH4Cl (2 mL) and partitioned in CH2Cl2 (15 mL) and water (15 mL). The aqueous layer was extracted with CH2Cl2 (2  15 mL). The combined organic extracts were dried (Na2SO4), and concentrated. The resultant residue was analyzed by 1 H NMR (400 MHz). Both the diastereoselectivity (dr) and the conversion are summarized in Table SI-3. Eventually, the crude mixture was purified by flash column chromatography to afford the desired products and the enantioselectivity (ee) of the reaction was then analyzed using chiral HPLC.
The reaction mixture was quenched with sat NH4Cl (2 mL) and partitioned in CH2Cl2 (15 mL) and water (15 mL). The aqueous layer was extracted with CH2Cl2 (2  15 mL). The combined organic extracts were dried (Na2SO4), and concentrated. The resultant residue was analyzed by 1 H NMR (400 MHz).
Both the diastereoselectivity (dr) and the conversion are summarized in Table SI-4.
Eventually, the crude mixture was purified by flash column chromatography on silica gel to afford the desired products and the enantioselectivity (ee) of the reaction was then analyzed using chiral HPLC.  athmosphere. Then, neat TMSOTf (1.3 equiv) was added dropwise to the stirring green-brown solution followed by 2,6-lutidine (1.5 equiv) addition, and the resultant mixture was stirred at 0 °C until completion.
For a 0.5 mmol scale reaction, the mixture was quenched with sat NH4Cl (2 mL) and partitioned in CH2Cl2 (15 mL) and water (15 mL). The aqueous layer was then extracted with neat CH2Cl2 (2 × 15 mL), and the combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Finally, the crude residue was purified by flash column chromatography to yield the named compound as a single enantiomer.
The syn/anti diasteromeric ratio (dr) is established in each case by 1 H NMR analysis of the crude mixture. Similarly, the enantiomeric purity (ee) of the syn compound isolated is established by chiral HPLC analysis of the purified products of both the racemic and the enantioselective reactions.
The reaction was also carried out at gram scale following the general procedure with 780 mg of 4 (4.5 mmol). The residue (dr 90:10) was purified as described to obtain 1.13 g of adduct 4a (
White solid.